Preparation of 21-brominated pregnanes



United States Patent 3,129,219 PREPARATION 0F ZI-BROh/HNATED PREGNANESRobert Joly, Montmorency, Seine-et-Oise, Julien Warnaut,Neuiliy-sur-Seine, .lean Jolly, Fontenay-sous-Bois, Seine, ArmandGuiliemette, Noisy-le-Sec, Seine, and Bernard Goflinet, Paris, Seine,France, assignors, by mesne assignments, to Roussel UCLAF, S.A., Paris,France, a corporation of France No Drawing. Filed Dec. 18, 1961, Ser.No. 160,294 Claims priority, application France Dec. 22, 1960 13 Claims.(Cl. 260-2395) The invention relates to a novel process for thepreparation of 21-bromo-pregnanes of the formula ot er (1) wherein R isselected from the group consitsing of hydrogen and methyl and wherein Ris selected from the group consisting of hydrogen and hydroxy' and Xrepresents the A, B and C rings of a pregnane molecule selected from thegroup consisting of Swpregnane, S/B-pregnane and 4fluoro-A*-pregnene.The invention also relates to the novel 21-bromo-steroids.

The present application is a continuation-in-part application of US.patent application Serial No. 124,247, filed May 3, 1961, now abandoned.

The bromination steps described in the piror art are not satisfactory.Upon treating pregnane-17-o1-20-ones which do not have a 3-one group ina chlorinated solvent such as chloroform with bromine in the samesolvent, a mixture of the starting steroid, the 21-brorninated steroidand the Zl-dibrorninated steroid is obtained. mixture is difiicult topurity and it is necessary to carefully eliminate the ZI-dibrominatedsteroid before cforming the 2.1- acyloxy steroid so as not tocontaminate the final product with the 21-diacyloxy steroid.

When bromiinating pregnane-ZO-ones 'which do not possess a 17-hydroxygroup such as 50:- or 5fi-pregnane-3- ol-20-one and Suor5fl-pregnane-3+ol-1 l,2O-dione to form the acetate ofdesoXy-corticosterone and dehydrocorticosterone, respectively, accordingto the prior art process, it is necessary to first form the17-bromo-steroid. The 17-bromo group must be later eliminated and theprocess, therefore, requires \two extra steps.

Moreover, in order to operate the bromination in the desirablehomogeneous phase, large volumes of solvent are required and, therefore,large apparatus is needed. Also, the large amount of solvent has to beremoved. The French Patent 1,127,897 discloses an attempt to overcomethe inconveniences in the bromination of 17-hydroxy-steroids by adding asmall amount of ethanol to the non-polar solvent and forming first acomplex with hydrochloric acid in the non-polar solvent. How ever, theyields of pure 21-brominated steroid are not high.

When brominating N-pregnene-ZO-ones having a fluorine group attached tothe 4 position, a bromination in the 6 or 2 positions would be expecteddue to the activation of the 4-fluoro-A group.

It is an object of the invention to provide a process for thepreparation of compounds of Formula 1 in high yields.

It is a further object of the invention to provide a process for thepreparation of compounds of Formula I without the prior artdisadvantages.

It is another object of the invention to obtain novel 21- 3,129,219Patented Apr. 14, 1964 lbrominated pregnane steroids and ZI-brominated Apregnene steroids.

These and other objects and advantages of the invention will becomeobvious from the rfollowving detailed description.

The process of the invention comprises reacting a pregnane compound ofthe formula:

wherein R, R and X have the above definitions with bromine in methanolin the presence of an enolization agent to form the corresponding21-br0mo steroid compounds and recovering the said product. In the caseof 17-ihydroxylated steroids no ZI-dibromo product is formed and in thel7-non-hydroxy1ated steroids, the 2l-brom0 product is the predominantproduct. The reaction scheme is illustrated in Table -I.

upon bromination forms the corresponding ZO-bromollbromo-pregnane or A-pregnene-20-ol which immediately reacts with the methanol to form thecorresponding 20- methoxy-Zl-bromo-pregnane or A -pregnene-20 ol. Thelatter compound then forms the desired ll-bromo-ZO-one steroid compound.The bromination may be carried out at temperatures between about 0 and50 C., preferably about 30 C. and care should be taken to avoid anexcess of bromine. This is best accomplished by stepwise addition ofbromine.

The reaction can be conducted in either the homo geneous phase or theheterogeneous phase and the phase will depend upon the solubility of thestarting pregnane-ZO- one or 4-fluoro-A pregnene-20-one. Since thesolubility of the starting steroid compound does not affect thereaction, it is possible to a l-Way's operate in small volumes as largeamounts of solvent are not required to dissolve the starting steroid.

The recovery of the Zl-bromo-ZO-one compound after the conclusion, ofthe reaction is a simple matter. Upon pouring the reaction mixture intoWater, the 21-brom0-20- one compound precipitates and is separated bydecanta- 3 tion or filtration. The product can be usually purified bysimply washing with water.

Suitable enolization agents are strong acids or acid halides. Examplesof enolization agents useful in the process are p-toluene sulfonic acid,gaseous hydrochloric or hydrobromic acids and organic acid chloridessuch as acetyl chloride.

The starting compounds of the process have the formula:

wherein R, R and X have the above definitions. The A, B, C or D ringsmay be substituted with hydroxy, keto groups, lower alkoxy, lower alkylor halogens. Examples of suitable starting materials are5fi-pregnane-3a,17a-diol- 20-one, SB-Pregnane-Ba,l7a-diol-11,20-dione,5fi-pregnane-3a-ol-20-one, 5p pregnane-3a-ol-l1,20 dione, 5 OC-pregnane-Iifl,l7u-diol-20-one, 4-fluoro-A -pregnene-1704-01- 3,11,20-trione, 4-filuoro-16a-methyl-A -pregnene-3,1 1,20- trione, etc.Other pregnane-20-ones and 4-fluoro-A -pregnene-20-ones are alsosuitable.

The 21-bromo compounds of Formula I are valuable intermediates for thepreparation of corticosteroids which have a 21-hydroxyl or a 21-acyloxygroup having 1 to 18 carbon atoms by the reaction of the 2l-bromocompounds with an alkali metal salt of an organic acid indimethylformamide to form the 2l-acyloxy compounds which may besaponified to the 21-hydroxyl compound. The 21-hydroxyl compounds maythen be further reacted such as by reduction, etc. to form other steroidcompounds.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

Example I PREPARATION OF THE 21-BROMO-5fl-PREGNANE- 311,17a-DIOL-20-ONETo a mechanically agitated suspension of 2 gm. of 5 8-pregnane-3a,l7a-diol-20-one in 10 cc. of methanol heated to 27 C., therewas introduced 0.1 cc. of anhydrous methanol containing of dryhydrochloric acid. Then the bromination was initiated by addition ofseveral drops of bromine. This operation of initiation was repeated asecond time after the disappearance of the bromine. Then in a period ofto 40 minutes, there was introduced 1 gm. of bromine without letting thetemperature of the reaction mixture rise above 26 to 28 C. The steroidwas completely dissolved at the end of 20 minutes.

The finish of the bromination was verified by starch iodine paper andthe reaction mixture was poured with mechanical agitation into a mixtureof water and ice con taining 0.2 cc. of a solution of commercial sodiumbisulfite in order to destroy the slight excess of bromine. Thehydrobromic acid liberated was neutralized to a pH of 7 by the additionof an aqueous solution of sodium bi- .carbonate. The agitation wascontinued for some time while maintaining the temperature at about 0 C.The mixture was filtered and the precipitate washed with hot water untilthere were no halides in the wash water. 2.47 gm. of2l-bromo-5/3-pregnane-3a,l7a-diol-20-one were obtained, being a yield of100% of pure product, having a melting point of 219 C., a specificrotation (c.=1% in chloroform), and containing 19.3 to 19.4% of bromine(theoretical: 19.33%).

4 Exam ple II PREPARATION OF 21-BROMO-5B-PREGNANE-3a,l7a-DIOL-11,20-DIONE With mechanical agitation 4 gm. of5B-pregnane-3a,l7- diol-11,20-dione were introduced into 16 cc. ofmethanol while elevating the temperature of the suspension to 30 C. 0.2cc. of absolute methanol containing 20% anhydrous hydrochloric acid wasadded. The bromination was commenced as in Example I and 1.92 gm. ofbromine were added over a period of 40 to 50 minutes while externallycooling so that the temperature of the reaction mixture is not raisedabove 30 C. The excess of bromine was destroyed by the addition of 1.92gm. of sodium metabisulfite dissolved in 20 cc. of water.

The reaction mixture was agitated for some time and added to a mixtureof ice and water. The product was filtered and washed with a mixture ofequal parts of dichlorethane and water, then with water until the washwater was free of halides, filtered and dried. 4.86 to 5 gm. of2l-bromo5fl-pregnane-3a,17a-diol-11,20dione, 2% hydrated were obtained,being a yield of 97 to 100%. The product had a melting point of 218-219C. and a specific rotation [a] =8O:1 (c.=0.5% in chloroform). Theproduct contained 19.1% of bromine (theoretical: 19.3%).

Example 111 PREPARATION OF 21-BROMO-5fl-PREGNANE- 3a-OL-20-ONE 10 gm. of5/3-pregnane-3 a-o1-20-one were dissolved under mechanical agitation in70 cc. of pure methanol at a temperature of about 30 C. and 4 drops ofacetyl chloride were added. Then 0.3 cc. of a solution of bromine inmethanol containing 12.2% of bromine was introduced. The decolorationwas total in less than a minute. The bromination was again initiated by0.3 cc. of the same solution. Then 46.5 cc. of the same methanolicsolution of bromine were added after each decoloration at 30 C. for aperiod of 16 to 18 minutes so that there was never an excess of brominein the solution. (The solution was not allowed to turn red.) At the endthe solution turned yellowish-orange and the speed of absorption wasretarded. It was verified with starch iodine paper that an excess ofbromine was present.

The solution was rapidly poured into a mixture of water and ice. The21-brominated derivative crystallized. The solution was maintained 1hour between 0 and +5 C., vacuum filtered, and the precipitate washedwith water and dried. After recrystallization from isopropyl ether, the2l-bromo-S/i-pregnane-Soc-ol-20-one was obtained in a yield in excess of60%, having a block melting point of 139140 C. and a specific rotation[a] =+l25il.5 (c.=0.5% in chloroform).

Analysis.C H O Br; molecular weight=4l3.4. Cal culated: C, 63.46%; H,8.37%; Br, 20.11%. Found: C, 63.5%; H, 8.3%; Br, 20.8%.

This compound is not described in the literature.

Exam ple IV PREPARATION OF 21-BROM0-5f3-PREGNANE- 3a-0L-11,20-DIONE Asolution of 10.6 gm. of 5/3-pregnane-3a-ol-1L20- dione in 70 cc. ofmethanol was prepared as in Example III. After the addition of severaldrops of acetyl chloride and initiation of bromination as in ExampleIII, 50.5 cc. of a methanolic solution of bromine of the sameconcentration were introduced stepwise. After precipitation in ice waterand drying, 12.5 gm. of 21-bromo-5fi-pregnane-3a-ol-11,20-dione wereobtained. By acetoxylation of the product with sodium acetate in adimethylformamide medium, the 21-acetoxy-5/8-pregnane-3a-ol-l1,20- dionewas formed with a yield greater than 60%. This latter compound is anintermediate in the synthesis of coiticosterone.

By operating Example IV except that Soc-pregnanc- 3B,l7oc-di0l-20-0ne isused as the starting material, 21- bromo-Sa-pregnane-BB,17a-diol-20-oneis obtained.

Example V PREPARATION OF 4-FLU0 RO-21-BR0M0-A PRE GNENE17a-OL-3,11,20-TRIONE Step A.10 gm. of A -pregnene-17a-ol-3,11,20-trionein 70 cc. of methanol were heated to reflux under agitation and anatmosphere of nitrogen. A mixture of 9 cc. of pyrrolidine and 10 cc. ofmethanol was added and the heating was continued for a period of fiveminutes. The reaction mixture Was cooled to C. and allowed to stand forseveral minutes at this temperature. Then the 3 -(N-pyrrolidyl)-A-pregnadiene-17a-ol-l1,20-dione was vacuum filtered. This product wasrecrystallized from petroleum ether. The yield was 11.1 gm. (being96.5%) of a product melting at 238 C. and having a specific rotation [a]Q=-143 (c.=0.5% in dioxane).

The product occurred in the form of pale yellow crystals, soluble inchloroform, methylene chloride and dioxane, slightly soluble in benzeneand insoluble in water, alcohol, ether and acetone.

Amount of nitrogen: 3.6%, theoretical being 3.52%. This product is notdescribed in the literature.

Step B. gm. of 3-(N-pyrro1idyl)-A -pregnadiene- 17a-ol-11,20-dione wereintroduced into 100 cc. of methanol. The solution was cooled to 20 C.and perchloryl fluoride was made to bubble through for a period ofminutes. The excess of perchloryl fluoride was removed by a stream ofnitrogen. The mixture was added to water and agitated for a period of anhour. The 4-fluoro- A -pregnene-17a-ol-3J1,2O-trione was vacuum filteredand recrystallized from refluxing acetone.

The product occurred in the form of white crystals having a meltingpoint of 260 C. and a specific rotation [a] =21 (c.=0.5% in chloroform).It was soluble in chloroform and methylene chloride, slightly soluble inalcohol, ether, acetone, benzene and methanol and insoluble in water.

Analysis.C H O F; molecular weight=362.43. Calculated: C, 69.58%; H,7.51%; F, 5.24%. Found: C, 69.7%; H, 7.5%; F, 5.49%.

This compound is not described in the literature.

Step C.--2 gm. of 4-fluoro-A -pregnene-17ot-ol-3,11,20- trione weredissolved in 20 cc. of dimethylformarnide. 2 cc. of pure hydrochloricacid were added thereto and the reaction mixture was allowed to standfor a period of 15 hours. After the addition of water, the 4-fluoro- A-pregnene-17a-ol-3,11,20-trione was vacuum filtered. The product had amelting point of 240 and 290 C. and a specific rotation [a] =+166(c.=0.5% in chloroform).

The product occurred in the form of white crystals and was soluble inchloroform and methylene chloride, slightly soluble in alcohol, ether,acetone and benzene and insoluble in water and methanol.

This compound is not described in the literature.

Step D.-S gm. of 4-fluoro-A -pregnene-17a-ol-3,11,20- trione wereintroduced into 75 cc. of methanol. 0.5 cc. of acetyl chloride was addedand the mixture was heated under agitation to 37 C. 7 cc. of a solutionof 14.2% bromine in methanol were added and the heating was continuedfor a period of a half hour. The reaction mixture was poured into amixture of water and ice and agitated for an hour at 0 C. The4-fluoro-21-bromo- A -pregnene-17a-ol-3,11,20-trione was vacuumfiltered. The yield was 5.78 gm. (being 95% of the theoretical).

This compound is not described in the literature.

The structure of this compound was confirmed by transformation of theproduct into the 21-acetoxylated derivative. By the action of sodiumacetate in a dimethylformamide medium, a product melting at 256 C. andhaving a specific rotation of [a] -=+2l3 (c.=0.5% in chloroform) wasobtained which is the acetate of 4- fluorocortisone.

6 Analysis.-C H O F; molecular weight=42 0.45. Calculated: C, 65.69%; H,6.95%; F, 4.52%. Found: C, 65.5%; H, 6.8%; F, 4.2%.

Ultraviolet spectra in ethanol A 246 mg.

Ett... 339

This compound is not described in the literature.

The free alcohol, 4-fluoro-cortisone, may be obtained by saponificationwith sodium bicarbonate in a methanolic medium.

The acetate of 4-fluoro-cortisone can be converted to 4-fluoro-cortisolby forming the 3,20-disemicarbazone, reducing the latter with potassiumborohydride and hydrolyzing the latter to 4-fiuoro-cortisol.

Example VI PREPARATION OF 4-FLUORO-2l-BROMO-lfia-ME-THYL-A4-PREGNENE-3,11,20-TRIONE 1.99 gm. of 4-fluoro-16a-methyl-A-pregnene-3,l1,20- trione (obtained according to United States patentapplication Serial No. 94,980, filed March 13, 1961) were introducedinto 20 cc. of methanol containing several drops of acetyl chloride.Then over a period of fifteen minutes, 1.10 gm. of bromine in a solutionof 11 cc. of methanol were added. The complete absorption of the bromineWas verified with starch iodine paper and the mixture was poured into amixture of water and ice. After addition of ordinary ether and isopropylether, the 4-fluoro- 21-bromo-16a-methyl-A -pregnene-3,11,20-trionecrystallized. The product was vacuum filtered, dried under vacuum and1.55 gm. of product were obtained (being 64% of the theoretical). Theproduct melted at 173 C.

This compound was not described in the literature.

The product obtained furnished after acetoxylation with sodium acetatein a dimethylformamide medium 4-fluoro- 21 acetoxy 16a methyl A pregnene3,11,20- trione, having a melting point of 215 C. and a specificrotation [a] ='+205 (c.=1% in chloroform).

Ultraviolet spectra=)\ 246 III/1., 6: 14,250.

Analysis.C H O F; molecular weight=418.5. Calculated: C, 68.87%; H,7.46%; F, 4.54%. Found: C, 68.7%; H, 7.2%; F, 4.7%.

This product can be transformed by sapom'fication with sodiumbicarbonate in a methanolic medium into 4-fluoro- 16a methyl A pregnene21 o1 3,11,20 trione having a melting point of 205 C. and a specificrotation [a] .=+207 (c.=1% in chloroform).

Analysis.C H O F; molecular weight=376.5. Calculated: C, 70.19%; H,7.76%; F, 5.05%. Found: C, 70.1%; H, 7.6%; F, 5.0%.

This compound as well as the acetate above mentioned ,is not describedin the literature.

4 fluoro 16a methyl A pregnene 21 ol3,11, 20-trione can be converted tothe corresponding llfi-h droxylated compound by formation of thedisemicarbazone, reduction of acid hydrolysis in the same manner as theacetate of 4-fluoro-co1tisone was changed to 4-fluorocortisol.

Various modifications of the process of the invention may be madewithout departing from the spirit or scope thereof, and it is to beunderstood that the invention is to be limited only as defined in theappended claims.

We claim:

1. A process for the preparation of a compound having the formula:

CHaBR wherein R is selected from the group consisting of hydrogen andmethyl, and wherein R is selected from the group consisting of hydrogenand hydroxy and X represents the A, B and C rings of a pregnane moleculeselected from the group consisting of Sfl-pregnanes, Set-pregnames and4-fiuoro-A -pregnenes which comprises reacting a compound having theformula wherein R, R and X have the above definitions with bromine inmethanol in the presence of an enolization agent selected from the groupconsisting of p-toluene sulfonic acid, mineral acids, organic acidhalides and inorganic acid halides to form the 21-bromo-pregnane andrecovering the latter.

2. The process of claim 1 wherein the enolization agent is a mineralacid.

3. The process of claim 1 wherein the enolization agent is an organicacid halide.

4. The process of claim 1 wherein the starting compound is5fi-pregnane-3a,l7a-diol-2l-one and the recovered product is21-bromo-5p-pregnane-3a,17a-diol-20- one.

5. The process of claim 1 wherein the starting compound isSfl-pregnane-Ba,17a-diol-11,20-dione and the recovered product is21-bromo-5 3-pregnane-3a,17u-diol-11, ZO-dione.

6. The process of claim 1 wherein the starting compound is5/8-pregnane-3a-oi-20-one and the recovered product is2l-bromo-Sfl-pregnane-Iia-ol-20-one.

7. The process of claim 1 wherein the starting compound is5,8-pregnane-3a-ol-11,20-dione and the recovered 5 product is21-bromo-5fi-pregnane-3u-ol-l1,20-dione.

8. The process of claim 1 wherein the starting compound is 4-fluoro-A-pregnene-17a-ol-3,l1,20-trione and the recovered product is4-fluoro-2l-bromo-A pregnene l7a-0l-3,1 1,20-trione.

9. The process of claim 1 wherein the starting compound is4-fiuoro-16a-methy1-A -pregnene-3,11,20-trione and the recovered productis 4-fiuoro-l6wmethyl-2lbromo-M-pregnene-BJ 1,20-trione.

10. 4 fluoro 21 bromo A pregnene 17oz ol- 3,11,20-trione.

11. 3 (N pyrrolidyl) A pregnadiene 17a o1- 11,20-dione.

12. 4 fluoro A pregnene 17o: ol 3,11,20-trione.

13. 4 fluoro A pregnene-17a ol 3,11,20-tri0ne.

References Cited in the file of this patent UNITED STATES PATENTSLaubach Jan. 21, 1958 Engel May 30, 1961 OTHER REFERENCES

1. A PROCESS FOR THE PREPARATION OF A COMPOUND HAVING THE FORMULA: